Process for the manufacture of steroid dehydrogenation products



llnited S s patm PROCESS FOR THE MANUFACTURE OF STEROID DEHYDROGENATIONPRODUCTS No Drawing. Application June 11, 1957 Serial No. 664,920

Claims priority, application Switzerland June 15, 1956 Claims. (Cl.260-3974) This invention relates to an improvement in the manufacture ofsteroid dehydrogenation products, especially of A 3-oxo-ster0ids of thepregnaneor androstane series, such as the well known highly activehormone compounds l-dehydro-cortisone and l-dehydro-hydrocortisone.

It is known that A -3-0xo-steroids are obtained when 3-oXo-steroids aretreated with selenium compounds having a dehydrogenating action. Inindividual cases, especially with certain 3-oxo-steroids saturated inthe ring A, this process is not entirely satisfactory since the yield ofA -3-oxo-compound leave something to be desired.

The present invention is based on the observation that the yields in theabove dehydrogenation can be improved when the dehydrogenation reactionis carried out in the presence of a metal of the second or eighth groupof the periodic system. A further feature of the invention is based onthe observation that from the mother liquors obtained by therecrystallization of the crude A -3-oxosteroids formed by the known orby the new process, further quantities of the desired final product canbe obtained when the residues of these mother liquors, ob-

- tained after separation of the purified crystalline A -3- oxo-steroidsand evaporation of the solvent are treated with nickel or iron and, ifdesired, subsequently again with the selenium compound ofdehydrogenating activity in the presence of a metal of the second oreighth group of the periodic system.

The process of the present application for the dehydrogenation of3-oxo-steroids to A -3-oxo-steroids by means of selenium compounds ofdehydrogenating activity is thus characterised in that thedehydrogenation is carried out in the presence of a metal of the secondor eighth group of the periodic system. A special feature of thisprocess consists in treating the selenium-containing fraction obtainedafter separation of the crystallized A 6- oXo-steroids obtained by thedehydrogenation of a 3-oxosteroid by means of a selenium compound havinga dehydrogenating action with nickel or iron, and if desired, subjectingthe reaction products again to a treatment with a selenium compound ofdehydrogenating action in the presence of metals of the second or eighthgroups of the periodic system.

Especially suitable metals are magnesium, zinc, cadmium, mercury andmanganese, iron, cobalt, nickel, which are used in finely divided form,care being taken during the dehydrogenation reaction that a thoroughmixing of the reacting materials takes place. The reaction productsobtained according to the present process, compared with the reactionproducts obtained Without the addition of metal, are less deeplycoloured and can be purified in a simpler manner.

From the selenium containing fraction of the reaction products, obtainedafter separation of the crystallized A -3-oxo-steroids, furtherquantities of l-dehydro-steroids can be obtained by treatment withnickel or iron 2,900,398 Patented Aug. 18, 1959 2 in a suitable solvent;deactivated Raney nickel is primarily suitable such as is obtained forexample by boiling active Raney nickel in a ketone such as acetone ormeth- V yl-ethyl ketone, and iron powder. A suitable solvent is forexample an alcohol or ketone. When nickel is used the crystallizedfractions obtained from the reaction product constitute a mixture of3-oxo-steroids which are completely or partially dehydrogenated in thering A, since under the conditions used the deactivated nickel iscapable of partial reduction of the A S-OXQ-grouping. For working up tothe desired A -3-oxo-steroids, the resulting reaction products aretherefore again treated with the selenium compound of dehydrogenatingaction, especially with selenium dioxide or selenious acid, in thepresence of a tertiary alcohol such as tertiary butanol or tertiary amylalcohol and of a metal of the second or eighth group of the periodicsystem.

The advantages that the new process offers can be seen from the examplesbelow. When, for example, 3,11,ZO-trioxo-l7a-hydroxy-2l-acetoxy-pregnane is dehydrogenated by the knownmethod with selenium dioxide, a reaction product is obtained from whichabout 40% of l-dehydro-cortisone acetate can be isolated. When thedehydrogenation is carried out in the presence of mercury or Zinc, theyield is increased to above 60%. On the other hand it was not hithertopossible to recover further crystallized fractions from the motherliquors of l-dehydro-cortisone or its Zl-esters (obtained bydehydrogenation of cortisone, 3,11,20-trioxo-l7a-2l-dihyd-roxypregnane,3,1 1,20-trioxo-l704,2l-dihydroxy-allopregnane, or its Zl-esters by theknown selenium dioxide process By treatment of the residues of thesemother liquors with deactivated Raney nickel and renewed dehydrogenationof the reaction product with selenium dioxide, it is now possible by thepresent process to obtain a further quantity of about 410% ofl-dehydro-compound. Similar yield improvements may be achieved whenusing as starting materials 3-oxo-steroicls of the androstane or testaneseries, which represents a remarkable progress for instance in themanufacture of certain 17cc-SllbStlt11li8d ldehydro-testosterones withanabolic action, such as ldehydro-17u-methyl-testosterone.

The following examples illustrate the invention:

Example 1 To 1.21 grams of3,11,20-trioxo-l7u-hydroxy-21-acetoxy-pregnane in 20 ml. of tertiaryamyl alcohol and 1.0 ml. of glacial acetic acid, after the addition of1.2 grams of mercury, at reflux temperature and with brisk stirring,0.74 gram of selenium dioxide in 33 ml. of tertiary amyl alcohol isadded dropwise and the whole is boiled under reflux for 14 hours.Separated selenium, mercury selenide and mercury are filtered off, thefiltrate is diluted with ethyl acetate and the ethyl acetate solution isshaken with ammonium sulphide and sodium carbonate solution, dried andevaporated. From the residue, by crystallisation from acetone-ether,0.73 gram of 1-dehydro-con tisone acetate is obtained. 0.5 gram remainsof a noncrystallising mother liquor product.

The 0.5 gram of mother liquor product is stirred for 5 hours underreflux with 5 grams of a deactivated Raney nickel suspension prepared byboiling of active Raney nickel in methyl-ethyl ketone, and 50 cc. ofmethly-ethyl ketone. After removal of the nickel by filtration andevaporation of the solvent, 0.37 gram is obtained of crystalline residuewhich, as above described, is dissolved in 10 cc. of tertiary amylalcohol and 0.5 cc. of glacial acetic acid and dehydrogenated with 0.23gram of selenium dioxide in 10 cc. of tertiary amyl alcohol in thepresence of 0.5 gram of mercury. Working up by the method describedabove yields a further 0.12 gram of l-dehydro-cortisone acetate. Thetotal yield thus amounts to 0.85 gram of l-dehydro-cortisone acetate.

When the dehydrogenation is carried out without the addition of mercuryand the mother liquors are not fur ther treated according to the presentprocess, from 1.21 grams of the above starting material 0.43 gram of1-dehydro-cortisone acetate is obtained:

To 1.21 gram of 3,1l,ZO-trioxo-17a-hydroxy-21-acetoxypregnane in 20 ml.of tertiary amyl alcohol and 10 ml. of glacial acetic acid, at refluxtemperature and with stirring, 0.74 gram of selenium dioxide in 33 ml.or" tertiary amyl alcohol is added dropwise and the Whole is stirredunder reflux for 14 hours. The separated selenium is filtered E and thefiltrate diluted with ethyl acetate and the ethyl acetate solution iswashed with ammonium sulphide and sodium carbonate solution, dried andevaporated. From the residue, by crystallization from acetone, 0.43 gramof l-dehydro-cortisone acetate is obtained.

Example 2 When grams of cortisone acetate are dehydrogenated withselenium dioxide, as described in Helv. Chim. Acta 39, 734 (1956), 8.0grams of crystalline l-dehydrocortisone acetate and 2.0 grams of amother liquor product are obtained, from the latter of which neither bycrystallisation nor by other purification methods can furtherl-dehydro-cortisone acetate be obtained.

The 2.0 grams of mother liquor product are boiled for i 5 hours underreflux in 50 ml. of methyl-ethyl ketone with 20 grams of deactivatedRaney nickel and the product is filtered from nickel and evaporated. 1.0gram of a crystalline residue is obtained, consisting for the most partof cortisone acetate and l-dehydro-cortisone acetate.

This residue, as described in Example 1, is dehydrogenated in ml. oftertiary amyl alcohol and 1 ml. of glacial acetic acid in the presenceof 1 gram of mercury with 0.6 gram of selenium dioxide dissolved in 15ml. of tertiary amyl alcohol and the product is worked up. In thismanner a further 0.4 gram of ldehydro-cortisone acetate is obtained.

Example 3 A suspension of 30 grams of l7u-methyl-testosterone and 10grams of selenium dioxide in 600 cc. of tertiary amyl alcohol is treatedwith 60 grams of magnesium powder and 6 cc. of glacial acetic acid. Themixture is refluxed for 24 hours with good stirring in an atmosphere ofnitrogen, another 10 grams of selenium dioxide being added after 10hours. After some cooling, the suspension is filtered through some hyfioand washed thoroughly with ethyl acetate. The resulting brown solutionis evaporated in vacuo and the residue dissolved in ethyl acetate. Theethyl acetate solution is then washed with water, dried and evaporated.To remove any selenium still present, the residue is dissolved in 200cc. of methanol and mixed with 100 grams of iron powder and 2 grams ofactive carbon. The mixture is heated for 30 minutes with stirring underreflux, then filtered with suction, washed with methanol and thesolution evaporated in vacuo. The residue is then chromatographed on 900grams of aluminum oxide. The residues of the evaporated benzene andether fractions are treated with active carbon in methanol or acetone,evaporated again, and the residue recrystallized from a mixture ofacetone and ether. There are obtained 17.5 grams of pure1-dehydro-l7a-methyl-testosterone which melts at l63l64 C. From themother liquors there can be obtained at small quantity of the samel-dehydro-compound having a somewhat lower melting point. The furthereluates of the chromatography, obtained with ethyl acetate and acetone,when recrystallized from acetone, give 4.2 grams of a mono-seleniumderivative of l-dehydrotestosterone of melting point 282284 C.

3 When inthe dehydrogenation there are added 130 grams of iron powderinstead of the magnesium, there is obtained the same yield ofl-dehydro-l7a-methyl-testoster-r one and of mono-selenium derivative.However, if the same reaction is made without magnesium or iron thereare obtained on working up in the same manner only 4.5 grams ofl-dehydro-l7u-methyl-testosterone of melting point 163-164 C. and 19.5grams of the mono-selenium derivative of melting point 282-284 C.

Example 4 A suspension of 5 grams of l7u-ethinyl-testosterone, 3 gramsof selenium dioxide and 40 grams of iron powder in 400 cc. of tertiaryamyl alcohol and 4 cc. of glacial acetic acid is refluxed with stirringin an atmosphere of nitrogen for 48 hours, another 3 grams of seleniumdioxide being added after 24 hours. The reaction mixture is worked up asdescribed in Example 3. The residue which is obtained is chromatographedover 150 grams of alumina. The benzene and ether eluates are treatedtogether with some active carbon in methanol or acetone and thenrecrystallized from acetone or a mixture of acetone and isopropyl ether.There are obtained 2.8 grams of l-dehydro-l7a-ethinyl-testosterone ofmelting point 228233 C. From the mother liquors there can be isolatedsmall quantities of the same l-dehydro compound having a somewhat lowermelting point. From the further ethyl acetate and acetone eluates of thechromatography selenium-containing derivatives are obtained.

When in this reaction the iron powder is replaced by 20 grams ofmagnesium powder there is obtained under otherwise identical conditionsthe same yield of l-dehydro-17a-ethinyl-testosterone.

However, if the reaction is carried out in the absence of iron ormagnesium under otherwise identical conditions, only 550 mg. of the purel-dehydro-lh-ethinyltestosterone of melting point 228-233 C. can beisolated.

Example 5 To 5.0 grams of3,11,20-trioxo-l7-hydroxy-2l-acetoxyallopregnane in ml. of tertiary amylalcohol and 2.5 ml. of glacial acetic acid there are added dropwiseafter the addition of 1.2 grams of mercury, at reflux temperature andwith brisk stirring 6.9 grams of selenium dioxide in 70 ml. of tertiaryamyl alcohol, and the whole is boiled under reflux for 14 hours.Separated selenium mercury selenide and mercury are filtered off, thefiltrate is diluted with ethyl acetate and the ethyl acetate solution isshaken with ammonium sulfide and sodium carbonate solution, dried andevaporated. From the residue there are obtained by crystallization fromacetone-ether 3.1 grams of l-dehydro-cortisone acetate.

When the dehydrogenation is carried out in the same manner, but withoutthe addition of mercury, there are obtained from 5 grams of the abovestarting material 2.2 grams of l-dehydro-cortisone-acetate.

What is claimed is:

1. In a process for the dehydrogenation of steroids of the pregnane,androstane and testane series substituted in 3-position by an oxo groupand which are at most unsaturated in ring A in the 4,5-position by meansof selenium dioxide, the improvement wherein the dehydrogenation iscarried out in the presence of mercury.

2. Process according to claim 1, wherein the seleniumcontaining fractionobtained after separation of the crystallized A -steroid substituted byan oxo group in 3-position obtained by the dehydrogenation of a steroidsubstituted in 3-position by an oxo group and saturated at least in oneof the positions 1,2 and 4,5 by means of a selenium dioxide is treatedwith a member selected from the group consisting of nickel and iron.

3. Process according to claim 2, wherein the treat ment with a memberselected from the group consisting of nickel and iron is carried out inthe presence of a member selected from the group consisting of analcohol and a ketone.

4. Process according to claim 2, wherein the reaction products obtainedare again subjected to a treatment with selenium dioxide in the presenceof mercury.

5. Process according to claim 1, wherein there is used as startingmaterial a member selected from the group consisting of a 3-oxo-steroidof the pregnane and the allopregnane series.

6. Process according to claim 5, wherein 3,1l,20-trioxo-l7u-hydroxy-2l-acetoxy-pregnane is used as starting material.

7. Process according to claim 5, wherein 3,11,20-trioxo-17u-hydr0xy-2l-acetoxy-allopregnane is used as starting material.

8. Process according to claim 1, wherein there is used as startingmaterial a member selected from the group consisting of a 3-oxo-steroidof the androstane and the testane series.

9. Process according to claim 8, wherein there is used as startingmaterial 17u-methyl-testosterone.

10. Process according to claim 8, wherein there is used as startingmaterial 17-a-ethinyl-testosterone.

References Cited in the file of this patent Helv. Chem. Acta., vol. 39,1956, 734-742, Meystre 10 et al.

1. IN A PROCESS FOR THE DEHYDROGENATION OF STEROIDS OF THE PREGNANE,ANDROSTANE AND TESTANE SERIES SUBSTITUTED IN 3-POSITION BY AN OXO GROUPAND WHICH ARE AT MOST UNSATURATED IN RING A IN THE 4,5-POSITION BY MEANSOF SELENIUM DIOXIDE, THE IMPROVEMENT WHEREIN THE DEHYDROGENATION ISCARRIED OUT IN THE PRESENCE OF MERCURY.